The positioning of rTMS

Introduction

The 2020 RANZCP mood disorders guidelines (Malhi et al., 2021) provide a comprehensive account of the management of major depression. For a novel treatment to be featured as part of mainstream management, it is necessary that it demonstrates comparative efficacy to inform its positioning in any treatment algorithm. Usually, this is determined on the basis of clinical effect. But rTMS has been posited as a treatment for depression largely because of its mechanism of action and not because of its clinical effect. Indeed, it is yet to show efficacy in depressed patients other than those with significant resistance to pharmacological therapy. This poses difficulties for the positioning of rTMS in treatment guidelines as it cannot be defensibly instigated prior to the use of psychological or medication strategies but at the same time, it cannot be regarded as a substitute for ECT because of its inferior efficacy to ECT for patients not responding to less invasive treatments. Consequently, the College guidelines appropriately advocate that consideration only be given to rTMS after “a reasonable number of adequate trials of pharmacotherapy and psychological treatment Choices and adequate trials of Alternatives” have been provided, and that additionally, “for severe or psychotic depression, ECT is the preferred treatment” (Malhi et al., 2021).

In practice, when treating a depressive episode that has not resolved following comprehensive psychological intervention and/or pharmacotherapy, the next step is usually to review the formulation carefully (paying particular attention to the accuracy of diagnosis and potential causal and maintaining psychosocial factors) and then if indicated, consider a course of electroconvulsive therapy (ECT). It is at this point, because of greater tolerability, rTMS is thought to have potential as a nonconvulsive alternative especially when there is no urgent indication for ECT. This is why most studies examining the efficacy of rTMS in the treatment of depression, have been conducted in patients with some degree of treatment resistance. However, even in this group of patients rTMS has been found to be substantially less efficacious than ECT, and therefore clinically, it is important to bear in mind that growing access to rTMS should not delay the appropriate use of ECT (Chen et al., 2017).

Thus, the positioning of rTMS in the management of depression is an important matter of debate. And, in this brief paper, we argue that in terms of efficacy, the literature for rTMS is modest as compared to more established treatments for depression (psychological interventions, antidepressant medication, ECT), and that because of its comparative immaturity its use in the routine management of depression remains contentious.

Prior to expanding on these points, we commence by outlining the optimal management of depression.

The recommended management of depression

As detailed in recent College guidelines (Malhi et al., 2021) the ideal approach to managing depression is to lay a foundation with Actions, which include the provision of evidence-based psychological treatments (Cuijpers, 2017) supported by psychoeducation and lifestyle interventions. In some instances of depression, these measures alone will be sufficient, but if not, medication may also be required (either supplanting or, most effectively, in combination with psychological treatment), and specific Choices can be considered. Provision of pharmacotherapy involves a number of strategies (that we summarise as MIDAS – Medication choice, Increase of Dose, Augmentation, Switching), which if after a number of medication trials are unable to achieve a satisfactory outcome, may require a physical Alternative such as electroconvulsive therapy (ECT). It is important to note that this sequence is not prescriptive, and that in some instances, for example to treat psychotic symptoms, it may be necessary to begin management with ECT, or because of patient preference, treatment may commence with pharmacotherapy. Throughout management a key guiding principle is to maintain a ‘response perspective’ – a positive iterative patient-centred approach to identify, and where necessary, modify interventions to optimise long-term outcomes. These considerations, in conjunction with individual factors, ultimately determine the specific treatment pathway for any individual.

Determining order

Once a management strategy for the treatment of major depression has been selected, the sequence in which therapies should be considered must be determined, and this is decided on the basis of two principal factors plus some additional considerations.

First and foremost, is the all-important question of whether an intervention works (efficacy). Equally critical however, is the second question of whether the intervention can be well-tolerated and does not cause significant harm because of side-effects (tolerability). The ranking and order of particular treatments determined by these two key factors can then be adjusted further, depending on whether an intervention is best suited to a specific population of depressed patients (subtype). For example, a patient with melancholia featuring marked psychomotor retardation is unlikely to engage in psychological treatment, and therefore in this scenario, it may be best to consider medication or even ECT from the outset.

Sequencing of a treatment algorithm for depression can also be determined by mechanistic insights that indicate which clinical profile is most likely to benefit. For example, if it is clear that a life event (e.g., a loss) has precipitated a depressive episode and ongoing negative thoughts are centred upon this event and its consequences, then it is likely that targeted psychological treatment will be of most benefit. Alternatively, if considering medication, and in addition to depressive symptoms the illness is marked by anxiety, then an agent with serotonergic activity may be of greatest benefit and can be given preference. These types of adjustments that involve refining treatment parameters and determining the order in which interventions are prescribed, rely on knowledge of how various treatments work, which is dependent on evidence from research trials and clinical experience.

Introducing a new treatment into the armamentarium

Before a new treatment for depression can be implemented it must first demonstrate efficacy. In other words, it has to show that it works. The more unequivocally this can be achieved, the more likely it is to have uptake. This is naturally easier if there are no alternative treatments and no direct comparators. However, even in these circumstances, the new treatment has to show some clinical benefit, and have an acceptable side-effect profile so that it is reasonably safe in clinical practice. For example, when lithium was rediscovered by Cade, even he initially hesitated in treating patients because of concerns regarding cardiac toxicity. Mood stabilisers developed subsequently for the management of bipolar disorder have always had to show not only that they work (compared to placebo), but that they are at least as efficacious as lithium (non-inferiority), or that they address aspects of the illness that lithium does not (advantage).

In the management of depression, we now have three groups of therapies – psychological, pharmacological and physical – and in each there are well-established therapies that are widely accepted as having proven efficacy; Cognitive behavioural therapy (CBT), antidepressants and ECT. Furthermore, each treatment has specific actions that target particular clinical symptoms and help to define the populations they benefit most.

The landscape is perhaps clearest in physical therapies where the only established treatment is ECT by virtue of its unequivocal efficacy (Chen et al., 2017). In the psychological realm CBT leads the way, but there are additional therapies that are effective and have slightly different targets, e.g. Interpersonal therapy (Cuijpers, 2017). Some nuancing of these interventions can be achieved by altering their parameters. For example, in the case of ECT, the placement of electrodes and the amount of current administered can be adjusted to prescribe different courses of treatment. Similarly, in the case of CBT, the specific focus of cognitive restructuring and behavioural experimentation (for example) is tailored to the individual. The domain within which there is greatest overlap in clinical effect is undoubtedly pharmacotherapy, where there are nearly 30 antidepressants each with slightly different pharmacodynamic and pharmacokinetic profiles. Therefore, in addition to demonstrating efficacy and tolerability, any new antidepressant for the treatment of depression has to also show that it is at least comparable to other antidepressants in terms of overall benefit, while also having something new to offer (Cipriani et al., 2018). This is a high bar, but a reasonable one given the choice of agents already available.

rTMS

When considering the management of depression, the most fundamental question rTMS faces is where does it fit? As yet, this has not been empirically defined, and the main problem is the manner in which rTMS has been introduced as a potential therapy for depression. While most treatments for depression have initially been identified (often serendipitously) on the basis of an antidepressant effect and then subsequently tested and refined for clinical use, in the case of rTMS the clinical effect was postulated on the basis of investigational use. Indeed, one of the claimed strengths of rTMS as a new treatment for depression is its novel mechanism of action compared to existing treatments. Therefore, because rTMS has emerged from basic science research rather than from noteworthy clinical findings, supporting arguments for rTMS based on its purported novel mechanism of action invite sceptical attention.

Mechanism

Knowledge as regards the potential mechanism of action of rTMS stems from its investigational use. The basic idea is that by stimulating a region of the brain that forms part of a neural network thought to be important to the maintenance of a depressive state, key components of brain function can be modified so as to restore a normal mood state. However, our understanding of the neural networks that underpin depression is incomplete, and therefore the mechanisms of any potential antidepressant action of rTMS remain to be discerned. This is important to bear in mind, as it distinguishes rTMS from other treatments. This is because, even though we lack a complete understanding of the therapeutic mechanisms of psychological treatments, pharmacotherapy and ECT, their clinical efficacy became evident first and how any effect is produced, was a secondary concern.

The clinical effect of rTMS

With respect to the clinical use of rTMS, a key problem is that it was initially envisaged as a non-convulsive alternative to ECT. As a consequence, most rTMS research in the treatment of depression “has been conducted in MDD patients with some form of treatment resistance” (Lefaucheur et al., 2020). But treatment-resistant depression (TRD) is both inadequately and variably defined and this has meant there is great heterogeneity in the published data as regards the parameters used for stimulation, the clinical populations studied, and the outcomes of studies; and because of this the evidence supporting its efficacy is limited.

Indeed, only rTMS applied to specific parts of the prefrontal cortex and at particular frequencies, holds some possibility of benefit, and even then, only if administered to depressed patients in an acute phase of a medication-resistant episode of illness. Importantly, there are no robust data concerning how to treat depression using rTMS beyond the acute phase of the illness and no clinical consensus either. In other words, the clinical data from recent trials is at odds with where rTMS is being prescribed in practice, namely, early in the sequence of treatments; before pharmacotherapeutic options have been adequately considered. However, on the basis of evidence, it would appear that rTMS should only be considered in those patients where all reasonable treatments have been properly trialled – including for example several courses of antidepressant pharmacotherapy. Furthermore, it is important to note that rTMS is not an alternative to ECT, and that its consideration should not delay the use of ECT where indicated.

Concluding remarks

Given that rTMS is being promoted as a treatment for depression largely on the basis of its tolerability and novel mechanism of action rather than its efficacy, a much deeper and clearer understanding of its effects is needed. Clinical equipoise studies are needed to empirically gauge the utility of rTMS relative to alternative therapeutic options, such as further medication trials, or adequate combinations of psychological and pharmacological interventions. Until such data is available, it is not possible to meaningfully position rTMS in the sequence of care for the routine management of depression. And until this happens, rTMS should remain an option mainly for those patients that have failed reasonable antidepressant treatments including augmentation strategies, and those who are not suitable for ECT, or have chosen not to pursue this treatment. Furthermore, the availability of rTMS should not interfere with the delivery of effective psychological and/or pharmacological treatment strategies and it should not delay the administration of ECT.